Method for the synthesis of irinotecan

Abstract

The present invention relates to a method for the synthesis of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (i.e. iriniotecan), comprising: (a) preparing 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptotecin; and (b) selectively ethylating the compound of step (a) at the 7-position, thus resulting in the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin. The present invention is further directed to the use of 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (i.e. 7-des-ethyl-irinotecan) as intermediate in a method for the synthesis of irinotecan as described.

The invention claimed is: 
     
       1. A method for the synthesis of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin having the structure according to Formula (1), the method comprising: 
       
         
           
           
               
               
           
         
         (a) preparing 10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin by contacting 10-hydroxycamptothecin with chlorocarbonyl-4-piperidinopiperidine hydrochloride; and 
         (b) selectively ethylating the compound obtained in step (a) at the 7-position, thus resulting in the preparation of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin. 
       
     
     
       2. The method of  claim 1 , wherein step (a) is performed in acetonitrile in the presence of at least one alkali metal carbonate or of a strong organic base. 
     
     
       3. The method of  claim 2 , wherein step (a) is performed in the presence of an alkali metal carbonate selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Rb 2 CO 3 , and Cs 2 CO 3 . 
     
     
       4. The method of  claim 2 , wherein step (a) is performed in the presence of a strong organic base and wherein said strong organic base is triethylamine. 
     
     
       5. The method of  claim 1 , wherein step (a) is performed at a temperature in the range between 20° C. and 80° C. 
     
     
       6. The method of  claim 1 , wherein step (b) is performed in the presence of ferrous sulfate, hydrogen peroxide, and propionic aldehyde. 
     
     
       7. The method of  claim 5 , wherein step (a) is performed at a temperature of 60° C.